The compound N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexahydrospiro[benzofuro[2,3-a]-quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfonamide is a peripherally acting selective α2-adrenoceptor antagonist, known also by codes of MK-467 and L-659,066. It has the chemical formula I presented below, as hydrochloride salt.

Several processes have been proposed in the art for the manufacture of the compound N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexahydrospiro[benzofuro[2,3-a]-quinolizine-2,4′-imida-zolidine]-3′-yl)ethyl)-methanesulfonamide.
EP 0259092 discloses a five-step process where, in the first step acetylethylenediamine is reacted with methanesulfonyl chloride to obtain 2-methanesulfonylaminoethylacetamide. In the second step 2-methanesulfonylaminoethylacetamide is treated with hydrochloric acid to obtain 2-(aminoethyl)methanesulfonamide. In the third step (12bS)-1,3,4,6,7,12b-hexa-hydrobenzo[b]furo[2,3-a]quinolizin-2-one is allowed to react with 2-(amino-ethyl)methanesulfonamide, followed by treating with diethyl cyanophosphonate to obtain the intermediate (2R,12bS)-2-cyano-2-(2-methanesulfonamidoethyl)amino-1,3,4,6,7,12b-hexahydrobenzo[b]-furo[2,3-a]-quinolizine. In the fourth step (2R,12bS)-2-cyano-2-(2-methanesulfonamidoethyl)amino-1,3,4,6,7,12b-hexahydrobenzo[b]-furo[2,3-a]-quinolizine is reduced using lithium aluminum hydride to obtain the intermediate (2R,12bS)-2-amino-methyl-2-(2-methanesulfonamidoethyl)amino-1,3,4,6,7,12b-hexahydrobenzo[b]furo[2,3-a]-quinolizine, which is treated in the fifth step with 1,1′-carbonyldiimidazole to obtain the product N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexahydrospiro[benzofuro[2,3-a]-quinolizine-2,4′-imidazoli-dine]-3′-yl)ethyl)-methanesulfonamide, which is converted to the corresponding hydrochloride salt. The starting material (12bS)-1,3,4,6,7,12b-hexahydrobenzo[b]furo[2,3-a]quinolizin-2-one was obtained from the corresponding rasemic compound using acylated L-tartaric acid, such as di-para-toluoyl-L-tartaric acid. This process of EP 0259092 contains several steps and many of them are not suitable for manufacture on a larger industrial scale. Chromatographic methods used for purification are not regarded as appropriate methods on larger scale. In the third step the aminocyanation is carried out using diethyl cyanophosphonate, whereby large amounts of salts are formed and complicated measures are needed for isolating the formed intermediate, whereby losses are typically about 15% or even higher and impurities are formed. Additionally, the salts are regarded as problem waste, which is costly to discard. Further, the reaction is slow, typically it takes about 3 days, which results in increase of the undesired diastereomer and decreases the yield too. Diethyl cyanophosphonate is an expensive reagent and its availability is poor. The use of lithium aluminum hydride in the reduction in the fourth step is hazardous and not suitable for industrial scale.
U.S. Pat. No. 4,942,235 describes an improved process where (2R,12bS)-2-cyano-2-(2-methane-sulfonamido-ethyl)amino-1,3,4,6,7,12b-hexahydrobenzo[b]-furo[2,3-a]-quinolizine, the intermediate obtained in third step of the process of EP 0259092, is first allowed to react with 1,1′-carbonyldiimidazole in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene to obtain (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzo-furo[2,3-a]quinolizine-2-carbonitrile, which is reduced with hydrogen in the presence of Raney nickel to obtain N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexahydrospiro[benzofuro[2,3-a]-quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)methanesulfonamide, which is converted to the corresponding hydrochloride with a mixture of acetyl chloride and methanol.
There is an evident need for an improved process for the manufacture of spirocyclic substituted benzofuroquinolizines, particularly N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexa-hydrospiro[benzofuro[2,3-a]quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfonamide.